Emerging roles of TEAD transcription factors and its coactivators in cancers.

Pobbati AV, Hong W - Cancer Biol. Ther. (2013)

Bottom Line:
They facilitate cancer progression through expression of proliferation promoting genes such as c-myc, survivin, Axl, CTGF and Cyr61.Given the fact that TEADs and their coactivators need to work together for a functional outcome, disrupting the interaction between them appears to be a viable option for cancer therapy.Structures of TEAD-coactivator complexes have been elucidated and will facilitate drug design and development.

ABSTRACTTEAD proteins are transcription factors that are crucial for development, but also play a role in cancers. Several developmentally and pathologically important genes are upregulated by TEADs. TEADs have a TEA domain that enables them to bind specific DNA elements and a transactivation domain that enables them to interact with coactivators. TEADs on their own are unable to activate transcription and they require the help of coactivators. Several TEAD-interacting coactivators are known and they can be classified into three groups: (1) YAP and its paralog TAZ; (2) Vgll proteins; and (3) p160s. Accordingly, these coactivators also play a role in development and cancers. Recent studies have shown that TEADs and their coactivators aid in the progression of various cancers, including the difficult to treat glioblastoma, liver and ovarian cancers. They facilitate cancer progression through expression of proliferation promoting genes such as c-myc, survivin, Axl, CTGF and Cyr61. There is also a good correlation between high TEAD or its coactivator expression and poor prognosis in various cancers. Given the fact that TEADs and their coactivators need to work together for a functional outcome, disrupting the interaction between them appears to be a viable option for cancer therapy. Structures of TEAD-coactivator complexes have been elucidated and will facilitate drug design and development.

Figure 3: Figure 3. Cartoon depicting the interaction among YAP/TAZ, Vgll proteins and TEAD. The TEAD-binding region of YAP/TAZ and Vgll proteins are represented as spirals. It adopts a similar structure and fits in the same groove on the surface of TEAD despite having a different primary sequence. YAP/TAZ and Vgll proteins pair with TEAD and upregulate gene expression. CTGF, Cyr61, c-myc and Axl are some of the genes that are upregulated by YAP and TAZ. YAP/TAZ play a significant role in proliferation, organ size and stem cell maintenance. Vgll proteins upregulate the expression genes such as IGFBP-5, myosin heavy chain (MyHC) and VEGFA. They play a role in proliferation, myogenesis and also appear to act as tumor suppressors in certain scenarios.

Mentions:
Despite similar structural interaction the gene expression mediated by these coactivators appears to be different (Fig. 3). There is data from limited set of genes that suggests YAP-dependent gene expression is different from that of Vgll-dependent gene expression.65 This is also seen in Drosophila, the YAP ortholog Yorkie upregulates genes such as diap1 and cyclinD, whereas Vg upregulates wing-specific genes. This is remarkable because YAP/TAZ/Yorkie and Vg/Vgll proteins do not have a DNA-binding domain and use the same transcription factor TEAD to mediate gene expression. The specificity in gene expression is unlikely to be solely determined by a transcription factor. The DNA recognition sequence of a transcription factor is often too short or degenerate and could be found everywhere in the genome. In order to enhance or alter specificity transcription factors often pair with other transcription factors or transcription coactivators. In the case of Vg and Vgll proteins, it is already known that they are endowed with the ability to alter the specificity of TEAD87 and this is likely to be the underlying reason for the differential gene expression. Altered specificity could result in differential promoter occupancy and gene expression. Future studies aiming to resolve the molecular basis for the differential expression by different co-activators on the same transcriptional factors will be of great interest and significance.

Figure 3: Figure 3. Cartoon depicting the interaction among YAP/TAZ, Vgll proteins and TEAD. The TEAD-binding region of YAP/TAZ and Vgll proteins are represented as spirals. It adopts a similar structure and fits in the same groove on the surface of TEAD despite having a different primary sequence. YAP/TAZ and Vgll proteins pair with TEAD and upregulate gene expression. CTGF, Cyr61, c-myc and Axl are some of the genes that are upregulated by YAP and TAZ. YAP/TAZ play a significant role in proliferation, organ size and stem cell maintenance. Vgll proteins upregulate the expression genes such as IGFBP-5, myosin heavy chain (MyHC) and VEGFA. They play a role in proliferation, myogenesis and also appear to act as tumor suppressors in certain scenarios.

Mentions:
Despite similar structural interaction the gene expression mediated by these coactivators appears to be different (Fig. 3). There is data from limited set of genes that suggests YAP-dependent gene expression is different from that of Vgll-dependent gene expression.65 This is also seen in Drosophila, the YAP ortholog Yorkie upregulates genes such as diap1 and cyclinD, whereas Vg upregulates wing-specific genes. This is remarkable because YAP/TAZ/Yorkie and Vg/Vgll proteins do not have a DNA-binding domain and use the same transcription factor TEAD to mediate gene expression. The specificity in gene expression is unlikely to be solely determined by a transcription factor. The DNA recognition sequence of a transcription factor is often too short or degenerate and could be found everywhere in the genome. In order to enhance or alter specificity transcription factors often pair with other transcription factors or transcription coactivators. In the case of Vg and Vgll proteins, it is already known that they are endowed with the ability to alter the specificity of TEAD87 and this is likely to be the underlying reason for the differential gene expression. Altered specificity could result in differential promoter occupancy and gene expression. Future studies aiming to resolve the molecular basis for the differential expression by different co-activators on the same transcriptional factors will be of great interest and significance.

Bottom Line:
They facilitate cancer progression through expression of proliferation promoting genes such as c-myc, survivin, Axl, CTGF and Cyr61.Given the fact that TEADs and their coactivators need to work together for a functional outcome, disrupting the interaction between them appears to be a viable option for cancer therapy.Structures of TEAD-coactivator complexes have been elucidated and will facilitate drug design and development.

ABSTRACTTEAD proteins are transcription factors that are crucial for development, but also play a role in cancers. Several developmentally and pathologically important genes are upregulated by TEADs. TEADs have a TEA domain that enables them to bind specific DNA elements and a transactivation domain that enables them to interact with coactivators. TEADs on their own are unable to activate transcription and they require the help of coactivators. Several TEAD-interacting coactivators are known and they can be classified into three groups: (1) YAP and its paralog TAZ; (2) Vgll proteins; and (3) p160s. Accordingly, these coactivators also play a role in development and cancers. Recent studies have shown that TEADs and their coactivators aid in the progression of various cancers, including the difficult to treat glioblastoma, liver and ovarian cancers. They facilitate cancer progression through expression of proliferation promoting genes such as c-myc, survivin, Axl, CTGF and Cyr61. There is also a good correlation between high TEAD or its coactivator expression and poor prognosis in various cancers. Given the fact that TEADs and their coactivators need to work together for a functional outcome, disrupting the interaction between them appears to be a viable option for cancer therapy. Structures of TEAD-coactivator complexes have been elucidated and will facilitate drug design and development.